ABSTRACT: Aging is characterized by the development of age-related metabolic diseases and frailty. Recent studies demonstrate that a decrease in levels of Nicotinamide adenine dinucleotide (NAD) is key causal factor for the development of age-related metabolic decline. NAD+ is crucial for oxi-reduction reactions and mitochondrial function. Interestingly, administration of NAD precursors such as nicotinamide mononucleotide (NMN) or nicotinamide riboside (NR) is sufficient to improve healthspan and longevity in mice. To date the mechanisms that lead to the NAD decline during aging has not been elucidated. The prevailing hypothesis is that activation of DNA-repair enzymes such as Poly-ADP-ribose polymerases (PARPs) would consume NAD during the aging process. However, we have recently challenged this paradigm and show that CD38 is the main NADase responsible for the aging-related NAD decline. The long term goal of my laboratory is to understand the role of CD38 in NAD metabolism during aging. CD38 is an ecto-enzyme that is highly expresses in inflammatory cells. CD38 expression and activity in these inflammatory cells is induced by cytokines and endotoxins. Thus our main hypothesis is that NAD decline, and metabolic dysfunction during aging is mediated by infiltration/accumulation of CD38+ inflammatory cells in tissues, that consumes NAD and its precursors via its ecto-NADase activity. Furthermore, we propose that cytokines derived from the ?chronic sterile inflammation of aging? are the main inducers of CD38 during the aging process. Finally, we propose that small molecule CD38 inhibitors (CD38i) can preserve cellular NAD levels, and augment metabolic health span in mammalians, and that CD38i will further increase resilience and longevity. In conclusion, CD38 may provide a mechanistic link between aging-related inflammation cellular NAD decline, mitochondrial and metabolic dysfunction. Furthermore, small molecule CD38i or CD38 blocking antibodies alone or in combination with NAD precursors may improve metabolic function and health span in the elderly.